Dengue virus (DEN), a NIAID bio-defense category A pathogen, causes dengue fever (DF) and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), the most prevalent arthropod-borne viral illnesses in humans worldwide. Due to the lack of an adequate animal model, the immunopathogenic mechanisms of DHF/DSS are presently unclear. We have optimized a mouse model for primary DEN infection and have determined that the murine interferon (IFN) system is more important than T and B cell dependent immunity for defense against primary DEN infection. Our long-term goal is to elucidate how the IFN system coordinates the anti-DEN immune response in mice. This proposal will test the hypothesis that IFNalpha/ beta producing plasmacytoid dendritic cells (PDCs) regulate the early immune response to primary DEN infection in mice. First, the role of PDCs in producing IFN-alpha/beta early during primary DEN infection in mice will be determined. Second, the role of IFN-alpha/beta in regulating natural killer (NK) cell proliferation, cytotoxicity, and production of IFN-gamma in mice with primary DEN infection will be examined. These two aims are designed to identify the major cellular source(s) and target(s) of murine IFNalpha/ beta in primary DEN infection and to determine their importance in limiting early viral infection. PDCs will be purified from tissues of uninfected and DEN-infected mice and examined for their production of IFNalpha/ beta and regulation of NK cell activities in both in vitro and in vivo settings. Loss-of-function models for murine PDCs and NK cells will be used to determine their relevance in mediating early viral clearance. A better understanding of the IFN-dependent immune response to DEN infection in mica may lead to the development of (i) a murine model that is more relevant to human DEN infection and disease, (ii) rational approaches for the design of anti-viral therapies and vaccines, and (iii) a greater understanding of the role of PDCs and the immune response to virus infections that are primarily controlled by the IFN system. [unreadable] [unreadable]